ABSTRACT Worldwide, lung cancer is the most common cancer and the leading cause of cancer-related deaths. While, cigarette smoking is the primary risk factor for this disease, only 15-20% of smokers will develop lung cancer. Moreover, we showed in the Multiethnic Cohort (MEC) Study that, on the average and for the same quantity of cigarette smoke, compared to whites, African Americans and Native Hawaiians have a 50% greater risk of developing lung cancer; whereas, Japanese Americans and Latinos have a 25% lower risk of the disease. In the prior funding period, we found that internal smoking dose, as measured by urinary total nicotine equivalents (TNE), was highest in African Americans and lower in Japanese Americans. This correlates with their population lung cancer risks. However, in Native Hawaiians and Latinos among biomarkers of internal smoking dose and tobacco toxicant exposure and metabolism, only the biomarkers for acrolein and crotoaldehyde correlated with directionality of lung cancer risk. Our preliminary DNA methylation data suggests that smoking dose may influence the epigenome differentially across racial/ethnic groups. Additionally, our preliminary analysis in MEC suggested that biomarkers of internal smoking dose over time (TNE-years) and of nicotine metabolism (cytochrome P450 2A6 activity) are associated with an increased risk of lung cancer, even after adjusting for self-reported measures of smoking dose (pack-years). The objectives of the proposed study are to identify biomarkers that are associated with smoking-related lung cancer risk and to improve our understanding of the mechanisms underlying the ethnic/racial differences in lung cancer risk. We propose to conduct an epigenome-wide association study of blood leukocyte DNA methylation with smoking dose and biomarkers of tobacco toxicant exposure and metabolism (Aim 1). We will also systematically investigate the association of biomarkers of tobacco toxicant exposure and metabolism (n=1,865 cases and 3,619 controls) and DNA methylation in blood leukocytes (n=1,600 cases and 3,354 controls) with lung cancer risk (Aim 2). Additionally, any biomarkers identified in the other projects (e.g. Projects 3 and 4: urinary DNA adducts of 1,3- butadiene, acrolein, and crotoaldehyde) that show a promise towards explaining the difference in disease risk will also be evaluated for potential associations with risk of lung cancer. We hypothesize that ethnic/racial and individual differences in lung cancer risk are due to disparate biological response to common tobacco lung toxicants, which will be reflected by variations in biomarkers of smoking dose, tobacco toxicant exposure and metabolism, and DNA methylation profiles. The findings from this study will expand our understanding of the smoking-related mechanisms of lung cancer and the ethnic/racial differences in lung cancer risk. The identification of risk biomarkers will aid in the development of novel smoking cessation interventions and targeted lung cancer screening efforts in high risk populations.